Abstract: An important challenge facing medicine today is the development of stem cell-based strategies for organ regeneration and repair. Many groups are investigating the genetic pathways and cell biological processes that regulate stem cells. However, the question of how stem cells and their niches evolved is dramatically understudied. Understanding the evolution of stem cells and their niches has the potential to transform the field of stem cell biology, because this knowledge will enable us to identify the genetic changes that trigger development of stem cells in a region where they are not present in ancestral species, and hopefully one day to harness this knowledge for therapeutic purposes. Fortunately, nature has provided us with an ideal system for exploring the mechanisms that underlie the ability of stem cells and their niches to evolve: continuously growing teeth. The goal of this proposal is to understand the genetic basis for the evolution of continuous growth of certain mammalian teeth. In this application, I describe a highly interdisciplinary project that includes comparative genomic, developmental and cladistic approaches. Together, these approaches will provide major new insights into the evolution of stem cell niches, using teeth as a model. The payoff of these studies will be both an improved understanding, at the basic level, of the genetics of stem cell evolution, as well as translationally relevant knowledge about dental stem cells that will be useful for organ bioengineering. Public Health Relevance: Tooth bioengineering is of great interest, because dental decay and tooth loss constitute an important public health issue. A thorough understanding of the molecular processes that drive tooth formation will be crucial to efforts to build new teeth. The mouse incisor, which is a continuously growing tooth, provides a genetically tractable system for understanding natural tooth renewal. We propose to use both evolutionary and developmental approaches to achieve a greater understanding of the regulation of stem cell-driven tooth renewal, and in the long run the results from these studies will be useful for engineering of teeth and other organs.